PROJECT SUMMARY/ABSTRACT (30 LINES MAX) The human gut is a unique site with enormous burden of foreign antigens from diet and microbes all the time. Among those antigens, the immune system should actively suppress inflammatory responses against harmless ones while mounting effector response to eliminate pathogens in case of their invasion. Imbalance of this pro- and anti-inflammatory responses in the intestine can lead to inflammatory bowel disease (IBD). Different subsets of T cells in the intestine can mediate both local pathogenesis and suppression of inflammation, and T cells use distinct strategies for homing to the small and the large intestine. While these homing processes have been considered as attractive therapeutic targets for IBD, ligand-receptor pairs specific for the large intestine are relatively unexplored. Our long-term goal is to characterize how T cell recruitment to the large intestine is accomplished. Our central hypothesis is that novel host protein C10orf99 is the ligand for homing receptors, such as GPR15, for the large intestine. Guided by strong preliminary data, we have generated novel mouse models that will enable us to test this hypothesis. We propose to pursue the following three aims: (1) To characterize the role of C10orf99 in T cell homing to the large intestine, we will test its role during physiological T cell activation and migration to the large intestine upon encountering microbial antigens in chronological order. To determine its relevance to colitis development, we will: (2) Examine the role of C10orf99 in the mouse model of colitis; (3) Characterize the expression pattern of C10orf99 within the large intestine and also during colonic inflammation in both mouse and human. Our findings will significantly advance understanding of T cell homing to the large intestine and will help to develop novel therapeutic strategies to treat inflammatory bowel disease.